1. Field of the Invention
The present invention relates generally to the fields of pharmacology and tumor biology. More specifically, the present invention relates to secretion of nucleoside diphosphate kinase (NDPK) from human tumors and the effects of inhibiting nucleoside diphosphate kinase activities.
2. Description of the Related Art
Cancer is the second leading cause of death in the United States, with one in four deaths attributed to the disease. Patients that succumb to breast cancer do so from the formation of metastatic tumors. Indeed, deaths due to colon, pancreatic, lung and other cancers are most often the result of metastatic disease rather than the consequence of the primary tumor per se (1).
Metastasis is a complex set of biological events involving proteolysis, cell motility, intravasation and extravasation, cellular communication, angiogenesis, and tumor growth. A great deal of recent interest has developed surrounding the need for metastatic tumors to develop blood supply from the host in order to grow and that on this basis, new cancer therapy can be developed (2).
The so-called metastasis suppressor gene, Nm23, may be an integral mediator involved in one or more of the events of metastasis. The description of the first human Nm23 gene (3) as a homologue of a Drosophila gene involved in the formation of the wing disk indicated a potential for metastasis inhibition and several studies have supported this claim.
Four Nm23 genes are encoded in human cells, with the two most highly studied being Nm23-H1 and Nm23-H2, encoding nucleoside diphosphate kinase-A (NDPK-A) and nucleoside diphosphate kinase-B (NDPK-B) respectively. Each of these enzymes, known to form homo-hexamers of 17.5 kDa (Nm23-H1) and 21.5 kDa (Nm23-H2) monomers, function primarily as a nucleoside diphosphate kinase (NDPK) in maintaining intracellular “housekeeping” by nonspecific trans-phosphorylation, and have later been found to have DNA binding activity and other non-nucleoside diphosphate kinase activities (4-7).
The enzymatic properties of the nucleoside diphosphate kinase are curious as these enzymes will bind a wide variety of both purine and pyrimidine triphosphates as phosphoryl donor and substrate. These enzymes, in the presence of divalent cations, covalently transfer the terminal γ-phosphate of a nucleoside triphosphate (NTP) to a nucleoside diphosphate (NDP) via a high-energy phosphohistidine intermediate: N1DP+N2TP N1TP+N2DP. The promiscuous nature of the enzyme may subserve its ability to act as a transphosphorylase transferring ATP from one cellular compartment to another.
It has been reported that nucleotides, particularly ATP derived from endothelial cells, are regulators of regional blood flow (8). Hence, it is hypothesized that there is a role for tumor-derived Nm23 in events supporting metastasis, particularly those of intravasation and extravasation of tumor cells that would be supported by the extracellular actions of nucleotides. The present invention provides evidences that support this hypothesis and further shows that inhibition of nucleoside diphosphate kinase activity may result in suppression of metastasis.